Central leptin gene delivery evokes persistent leptin signal transduction in young and aged-obese rats but physiological responses become attenuated over time in aged-obese rats

Scarpace, Philip J.; Matheny, Michael; Zhang, Y.; Tümer, Nihal; Frase, CD; Shek, Eugene W.; Hong, Bum–Kee; Prima, Victor; Zolotukhin, Sergei

doi:10.1016/s0028-3908(02)00003-5

Cited by 58 publications

(82 citation statements)

References 30 publications

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“…We have previously established a young lean rat model of leptin resistance that avoids the complications of obesity to address this issue [10]. In this model, central overexpression of leptin as a result of long-term rAAV-mediated gene delivery elevates the cerebrospinal fluid leptin level by 75% [9] and induces leptin resistance characterised by attenuated food and energy responses to the elevated central leptin and lack of these responses to exogenous leptin administration [10].…”

Section: Discussionmentioning

confidence: 99%

“…A small hole was drilled through the skull and a 23-gauge stainless steel guide cannula was inserted, followed by an injection cannula. A 3-μl volume was delivered using a 10-μl syringe [9].…”

Section: Experimental Design and Dietmentioning

confidence: 99%

“…In contrast, in lean rodents leptin evokes potent anorectic and thermogenic responses and produces marked lipopenia and weight reduction [6][7][8]. For example, chronic hypothalamic overexpression of leptin by recombinant adeno-associated viral-mediated central leptin (rAAV-leptin) delivery in young lean F344×BN rats reduces food intake and increases oxygen consumption, resulting in a dramatic loss of fat mass [9,10]. However, these leptin responses wane over time despite continued leptin transgene expression, and the decreased adiposity and weight loss are reversed, indicating the development of leptin resistance [10].…”

Section: Introductionmentioning

confidence: 99%

“…Paradoxically, irrespective of the development of this leptin resistance, the continued central overexpression of leptin induces persistent hypothalamic leptin signalling, as evidenced by elevated phosphorylation of signal transducer and activator of transcription 3 (P-STAT3) [9,11]. It follows from this that leptin resistance can be presumed to be downstream of STAT3 phosphorylation or resident in a parallel signalling cascade.…”

Section: Introductionmentioning

confidence: 99%

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Leptin resistance exacerbates diet-induced obesity and is associated with diminished maximal leptin signalling capacity in rats

et al. 2005

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Aims/hypothesis: Leptin resistance is generally considered a consequence of obesity. We postulated that leptin resistance is associated with diminished hypothalamic leptin signalling capacity and that leptin resistance is causal to obesity. We assessed maximal leptin-mediated binding of the transcription factor signal transducer and activator of transcription 3 (STAT3), and the response to high-fat feeding in lean leptin-resistant rats. Materials and methods: Recombinant adeno-associated virus encoding rat leptin cDNA (rAAV-leptin) or control vector were administered by intracerebroventricular injection to lean F344×BN rats for up to 150 days, and food consumption, body weight, serum leptin and glucose tolerance were measured. Leptin-mediated hypothalamic transcription factor binding was assessed at day 150 following an intracerebroventricular injection of 2 μg leptin. Rats pretreated with either control or rAAV-leptin vector for 94 days were given a high-fat diet, and energy intake, body weight gain and adiposity were examined. Results: The rAAV-leptin-treated rats initially responded to leptin gene delivery then became leptin-resistant. They displayed persistent submaximal hypothalamic leptin signalling and enhanced insulin sensitivity, yet maximal hypothalamic signalling capacity was decreased by more than 50%. On a high-fat diet, the leptinresistant rats consumed more energy, gained more weight and accumulated greater visceral fat mass than controls. Conclusions/interpretation: The maximal hypothalamic leptin signalling capacity was diminished in leptin-resistant rats receiving central rAAV-leptin gene therapy. Moreover, this leptin-invoked leptin resistance perturbs the regulation of energy homeostasis in response to high fat exposure, producing augmented energy consumption. This, coupled with potential hypersensitivity to insulin, creates a milieu favouring fat deposition. Our data suggest that leptin resistance is both a consequence and cause of obesity.

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Section: Discussionmentioning

confidence: 99%

Section: Experimental Design and Dietmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Leptin resistance exacerbates diet-induced obesity and is associated with diminished maximal leptin signalling capacity in rats

et al. 2005

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“…This increase in body weight with age is a major risk factor for insulin resistance, diabetes and ath-erosclerotic cardiovascular disease [15]. Aged mice and rats are associated with reduced hypothalamic Pomc expression [12], and the induction of Pomc by exogenous leptin is impaired with ageing [16]. The male F1 hybrid of Fischer 344-Brown Norway rats (F344/BN) is a useful model for age-related obesity because these rats have a relatively long lifespan and gain a substantial amount of body weight and fat mass with ageing [17].…”

Section: Introductionmentioning

confidence: 99%

Hypothalamic pro-opiomelanocortin gene delivery ameliorates obesity and glucose intolerance in aged rats

Zhang

Wilsey

et al. 2005

Diabetologia

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Aims/hypothesis: Age-related obesity is associated with impaired hypothalamic pro-opiomelanocortin (Pomc) gene expression. We assessed whether overproduction of POMC in the hypothalamus ameliorates age-related obesity in rats. Methods: Recombinant adeno-associated virus (rAAV) encoding Pomc (rAAV-Pomc) or control vector was delivered bilaterally into the basomedial hypothalamus of aged obese rats with coordinates targeting the arcuate nucleus. Energy balance, glucose metabolism, brown adipose tissue thermogenesis and mRNA levels of hypothalamic neuropeptides and melanocortin receptors were assessed. Results: Forty-two days after Pomc gene delivery, hypothalamic Pomc expression increased 12-fold while agouti-related protein and neuropeptide Y mRNA levels remained unchanged. Using a punch technique, we detected the highest Pomc RNA level in the arcuate nucleus. Pomc overexpression reduced food consumption from day 10 after vector injection, but this anorexic effect abated by day 30. In contrast, there was a steady decrease in body weight without apparent attenuation. Pomc gene delivery decreased visceral adiposity and induced uncoupling protein 1 in brown adipose tissue in aged rats. Serum NEFA and triglyceride levels were also diminished by rAAV-Pomc treatment. Improved glucose metabolism and insulin sensitivity were observed on day 36 but not day 20 after Pomc gene delivery. The expression of hypothalamic melanocortin 3 and 4 receptor decreased by 17% and 25%, respectively in rAAV-Pomc rats. Conclusions/ interpretation: This study demonstrates that targeted Pomc gene therapy in the hypothalamus reduces body weight and visceral adiposity, and improves glucose and fat metabolism in aged obese rats. Thus long-term activation of the central melanocortin system may be a viable strategy to combat age-related obesity and diabetes.

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Leptin, Obesity, and Leptin Resistance

Münzberg

Heymsfield

2014

Leptin

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Central leptin gene delivery evokes persistent leptin signal transduction in young and aged-obese rats but physiological responses become attenuated over time in aged-obese rats

Cited by 58 publications

References 30 publications

Leptin resistance exacerbates diet-induced obesity and is associated with diminished maximal leptin signalling capacity in rats

Leptin resistance exacerbates diet-induced obesity and is associated with diminished maximal leptin signalling capacity in rats

Hypothalamic pro-opiomelanocortin gene delivery ameliorates obesity and glucose intolerance in aged rats

Leptin, Obesity, and Leptin Resistance

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